Endocrine Unit

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Endocrine Unit: Bergwitz Laboratory

Our research focuses on inborn errors of phosphate metabolism and the endocrine regulation of phosphate homeostasis with an emphasis on the metabolic and homeostatic effects of phosphate.

Overview

Genetic Causes of Hypophosphatemia
In 2006, we identified the genetic defect underlying the childhood disorder hereditary hypophosphatemic rickets with hypercalciuria (HHRH). HHRH is caused by mutations in NaPi-IIc, a renal sodium-phosphate co-transporter, which is important to conserving phosphate in the kidney and leads to hypophosphatemia and rickets when lost. Our research goal is now to study the role of NaPi-IIc in human phosphate homeostasis and to understand the phenotypic variability of patients suffering from HHRH. For this purpose, we are currently using mammalian and Xenopus oocyte expression systems to study the functional properties of the identified human NaPi-IIc mutations in vitro. Plans for the near future are to establish mouse models to study the role of NaPi-IIc and some of the human mutations in vivo.

We also established international collaborations to look for NaPi-IIc mutations in new patients suffering from HHRH both to establish their molecular diagnosis and to carefully study their symptoms to see whether only some or all patients are at risk for developing kidney stones.

Metabolic and homeostatic effects of phosphate
A more recent research interest is in trying to understand how human and other metazoan cells sense inorganic phosphate to explain the effects of phosphate on:

  • Cell metabolism (metabolic sensing)
  • How phosphate feeds back to regulate the above hormonal systems (homeostatic sensing)
  • Whether  metabolic and homeostatic sensors use the same signal transduction cascades

For this purpose, we have performed a genome-wide Drosophila RNAi knockdown using phosphate-induced activation of MAPK (in vitro) in collaboration with Stephanie Mohr, Elizabeth Perkins and Norbert Perrimon of Harvard Medical School. We identified 103 genes, including 85 phosphate-specific genes and evaluated the genes in live flies with assays for dietary phosphate toxicity, hemolymph phosphate and life span. Our goal in the next five years will be to identify mammalian systems suitable to study phosphate sensing. The team will also continue exploring Drosophila melanogaster as a model organism. Relevant readouts for humans will be the homeostatic regulation of the synthesis and secretion of PTH, 1,25-D and FGF23 by phosphate and its metabolic effect on life-span in genetic disorders, such as familial hyperphosphatemic tumoral calcinosis (FHTC) and chronic kidney disease.

Clinical Work
I attend on the endocrine consult service at Massachusetts General Hospital and see outpatients with a focus on disorders of minerals and metabolism as a member of the Mass General Endocrine Associates. Furthermore, I also participate as faculty in the annual endocrine postgraduate course in Boston.

Past and Current Funding:

  • Young investigator awards by the National Kidney Foundation (2006-2008) and the American Society of Clinical Investigation (2007)
  • Mentored Research Award (K08) by the NIDDK/NIH (2007-2012)
  • Harvard Catalyst Grant (2009)
  • R03 and ARRA support by the NIDDK/NIH (2010-2011)

Group Members

Clemens W.H. Bergwitz, MD
Yuwen Li, MD

Local Collaborators

Harald Jüppner, MD
Chief, Pediatric Nephrology
MassGeneral Hospital for Children  

Stuart A. Forman, MD, PhD
Henry K. Beecher Pharmacology Laboratory
Massachusetts General Hospital Department of Anesthesia, Critical Care and Pain Medicine

Norbert Perrimon, PhD
Department of Genetics
Harvard Medical School, Howard Hughes Medical Institute
View Laboratory of Norbert Perrimon, PhD

Stephanie Mohr, PhD
Drosophila RNAi screening center

Elizabeth Perkins, PhD
Transgenic RNAi Project (TriP) , Drosophila RNAi Screening Center
Harvard Medical School

Bonnie Berger, PhD
Computation and Biology Group, Computer Science and Artificial Intelligence Lab, MIT

 Publications

View recent publications from the laboratory.  Some full text articles may require a subscription.
View all Publications in PubMed



 

 

Selected Reviews and Book Chapters

Dietary phosphate modifies lifespan in Drosophila. Bergwitz C Nephrol Dial Transplant 2012 Nephrol Dial Transplant 27: 3399–3406

FGF23 and syndromes of abnormal renal phosphate handling. Bergwitz C, Jüppner H. Adv Exp Med Biol. 2012;728:41-64.

Phosphate sensing. Bergwitz C, Jüppner H Adv Chronic Kidney Dis  2011;18:132

Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Bergwitz C, Jüppner H. Annu Rev Med. 2010;61:91-104.

Disorders of Phosphate Homeostasis and Tissue Mineralisation. Bergwitz C, Jüppner H. Endocr Dev. 2009;16:133-156.

Endocrine Unit Research Laboratories

Thier Building
50 Blossom Street
Boston, MA 02114

Phone: 617-726-3967
Fax: 617-726-7543
Hours: 9:00 am - 4:30 pm, M-F

Public Transportation Access: yes
Disabled Access: yes